The IL-12 family cytokines have emerged as an important group of cytokines that regulate many critical aspects of host immunity, including antigen presentation, T cell lineage commitment and cytokine signaling. IL-12 family cytokines are comprised of heterodimeric protein subunits. Unique combinations of subunits can form through covalent and non-covalent binding and these include IL-12 (IL12p40 & IL12p35), IL-23 (IL12p40 and IL23p19), IL-27 (IL27p28 & EBI3 and a novel pairing between IL12p35 and EBI3 now constitutes the newly described member, IL-35. Individual subunits (e.g. IL27p28) have also been shown to have intrinsic biological activities. Our research goal has been to generate various combinations of IL-12 cytokine family subunit chains as basis for a new class of therapeutic cytokines. In this regard we have genetically engineered novel IL-12-like cytokines by pairing IL12p40 to IL27p28 and EBI3 to IL23p19 and are now defining their potential biological activities on lymphocytes and ocular cells. Specifically, we intend to use these reagents to test each subunit and various subunit combination in T cell assays to determine if they exhibit any useful biological activities and eventually, to explore their use in treating ocular diseases. Another area of interest is regulation of the initiation, intensity and duration of signals emanating from these cytokines. We have shown that IL-35 induces Bregs in vivo and promotes the conversion of Bregs to a unique Breg subset that produces IL-35 (i35-Breg). In addition, we reveal that pre-existing GL7IL-10+ cells exist in nature and are expanded during inflammation, differentiating into GL7+ Bregs that suppress autoimmunity in mice. We have also identified and characterized a novel IL-23p19/Ebi3 (IL-39) cytokine mediates that mediates B cell-induced inflammation. We further show that topical administration of a SOCS1 mimetic peptide is effective in suppressing uveitis in mice.